This project studies the psychobiology of schizophrenia and attempts to develop improved strategies for its treatment. One goal is the understanding of the mechanism of action of neuroleptic drugs. We have observed that neuroleptic-induced time-dependent decrease in levels of plasma homoyanillic acid (HVA), a major dopamine metabolite, correlates with antipsychotic drug response, suggesting that slow to develop changes in dopamine turnover may underlie the antipsychotic action of neuroleptic. This clinically relevant dopamine marker is further studied using a strategy in which peripherally derived HVA is reduced by the administration of debrisoquin, a MAO inhibitor which does not enter the CNS. Longitudinal studies of the atypical neuroleptic, clozapine, have begun in/ and outpatient settings. This drug holds promise for enhancing the therapeutic effectiveness of neuroleptic treatment of schizophrenia and our studies are geared toward delineating fundamental mechanisms involved in its unique efficacy. In a recently completed study using magnetic resonance imaging (MRI) performed in collaboration with the Clinical Brain Disorders Branch, NIMH, compelling evidence was gained which supports enlargement of lateral and 3rd ventricular volumes in schizophrenic patients. A follow-up study of previous inpatients from our program has recently been completed and holds promise for delineating biological correlates of outcome in schizophrenia. Further studies of outcome are in progress. The development of extended pedigrees of families with high prevalence of schizophrenia is underway with the goal of establishing genetic linkage by RFLP techniques to the disease transmission. Collaboration with the NIMH positron emission tomography (PET) program focuses on the mechanism of action of typical and atypical neuroleptics using glucose utilization studies and on the development of new PET ligands.